Transmissible spongiform encephalopathies(TSE)diseases affect a wide range of species including sheep,cattle, mink, humans, deer, elk and others. An issue of particular importance is to determine which TSE diseases can be transmitted to other species especially humans or livestock. To investigate the issue of cross-species transmission we used an animal model involving transmission of hamster scrapie agent to mice (prior to our study mice were considered resistant to hamster scrapie). We found that cross-species transmission between supposedly incompatible hosts can occur but involves a very slow but relentless process requiring several passages in the new host before finally emerging as a recognizable disease. This persistance and eventual adaptation suggests that similar situations could occur in other species combinations. In the USA there is concern that chronic wasting disease of deer and elk could be transmissible to humans or other species by similar mechanisms. To study this particular possibility we inoculated non-human primates with CWD infected brain. If the non-human primates become sick the possibility that humans might be susceptible would also seem possible. Several of the animals were inoculated approximately 26 months ago but have not shown any clinical evidence of TSE-like disease. Animals were inoculated by either the intracerebral or oral routes. In order to study other aspects of CWD we have developed mice transgenic for deer prion protein. Several lines have been derived that make deer PrPsen and after inoculation with CWD brain homogenates derived from CWD infected deer or elk develop clinical disease and disease-associated PrP-res. These mice are being used to study several aspects of CWD including pathogenesis in infected animals and whether persistence occurs in seemingly uninfected animals. They are also being used to develop assays for CWD infectivity found in naturally infected animals or animal models. Several other kinds of transgenic mice have been used over the past few years to investigate a variety of questions regarding the influence of prion protein on interspecies transmission, the role of specific cell types on TSE pathogenesis and kinetics of disease development. It is known that interspecies transmission can involve prion protein interactions between the prion proteins (PrP) of the species involved. To determine how PrP influences transmission among species we have developed mice transgenic for hamster prion protein (HPrP). The HPrP has been expressed using a variety of promoters including the neuron- specific enolase promoter (NSE) which targets expression to neurons, the GFAP specific promoter to target expression to astrocytes and natural promoters which result in expression in many tissues. Each of these types of mice has been bred to PrP null mice which do not express mouse PrP. Thus, we have available several types of mice which we have used to investigate how expression of PrP in specific cell types influences susceptibility to scrapie and how HPrP and mouse PrP (MoPrP) interact. Mice which express HPrP under the control of natural or NSE promoters are completely susceptible to hamster scrapie agent following intracerebral inoculation. This result showed that PrP is critical to transmission and that expression restricted to neurons is sufficient for transmission to occur. If NSE/HPrP was expressed in mice which lacked functional MoPrP expression, the incubation period was reduced indicating that the presence of MoPrP in some way competed with HPrP to delay the onset of disease. The effect was protective for the mice in that disease was either delayed or completely circumvented. Mice which express HPrP under the control of the GFAP promoter (GFAP/HPrP) did not become clinically sick after inoculation of hamster scrapie agent. However, if GFAP/HPrP was expressed in mice which lacked MoPrP, expression they did become sick following hamster agent inoculation. This result suggested that astrocyte specific expression oof HPrP was also sufficient for transmission to occur though much less efficiently than was true if expression was limited to neurons. Furthermore, this result demonstrated very strong interference between MoPrP and HPrP in the mice which expressed both. Because TSE diseases are thought to be transmitted orally we also inoculated the NSE/HPrP Tg mice and another Tg line designated Tg7, where HPrP is expressed in multiple tissues, with hamster scrapie agent orally and intraperitoneally. Most of the mice inoculated by these routes survived if they expressed both mouse and HPrP. These results suggested that therapeutic intervention in TSE diseases could be based on these interference mechanisms. We have found that hamster scrapie agent can persist in mice for the mouse's lifespan but not cause clinical disease. (Previously mice were thought to be resistant to hamster scrapie agent). When brain or spleen tissue from clinically normal mice was passed to hamsters and additional mice the hamster recipients all died. Most of the mice remained clinically well but disease-associated prion protein accumulated in the brains of several of them indicating that mouse-adapted agent was forming. A third pass to hamsters and mice showed that hamster agent was still present. In addition mice representing one of the donors developed clinical disease after 180 days showing that some mouse adapted strains were evolving. Fourth passages have also been accomplished and shows further evidence for the evolution of specific strains. At least one of these is hamster specific another mouse specific and two additional strains are dual tropic for hamsters as well as mice. This data suggests that the same process could occur in other species and may explain the origin of BSE from sheep scrapie. It also should warn us that the same process could occur in the USA between or among cattle, sheep and wildlife.